tbuckley/cabot-search huggingface dataset:
Updated results from a phase 2 study on dalpiciclib and pyrotinib, a dual-oral chemotherapy-free regimen in HER2-positive advanced breast cancer (DAP-HER-01).
Authors: Min Yan, Limin Niu, Huimin Lv, Mengwei Zhang, Zhenzhen Liu, Xiuchun Chen, Zhenduo Lu, Chongjian Zhang, Huiai Zeng, Shengnan Zhao, Yajing Feng, Jing Wang, Huihui Sun, Huajun Li
Journal: Journal of Clinical Oncology (2023)

1045 Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown synergistic effect with anti-HER2 therapy on hormone receptor (HR)-positive and HER2-positive breast cancer from preclinical models and several clinical studies, while data of this combination in HR-negative and HER2-positive diseases are limited so far. DAP-HER-01 (NCT04293276) was aimed at evaluate the efficacy and safety of the novel dual-oral, chemotherapy-free regimen of CDK4/6 inhibitor dalpiciclib and pan-HER tyrosine kinase inhibitor pyrotinib in HER2-positive advanced breast cancer (ABC) regardless of HR status, and reported to meet the primary endpoints previously (overall ORR 70%), in which HR-negative patients achieved a higher ORR (81.8%, vs 55.6% in HR-positive patients; Min Yan, et al. ESMO 2021, Poster 276P). Here we reported the updated results of this trial. Methods: DAP-HER-01 was a single-arm, phase 2 study conducted in HER2-positive ABC patients with no more than one prior systemic treatment at advanced setting. Enrolled patients received dalpiciclib and pyrotinib until progression, unaccepted toxicity, or no further benefit. The primary endpoint was ORR as per RECIST 1.1, and secondary endpoints included progression-free survival (PFS), overall survival and safety. Results: Between April 9, 2020, and May 19, 2021, 41 patients were enrolled and received study treatment, and 40 of them were assessable for efficacy. With a median follow-up of 19.2 months, the median progression-free survival (PFS) was 11.0 months (95% CI 7.3-19.3). Considering HR status, the PFS in HR-negative patients was not matured (estimated median: 16.6 months; 95% CI: 7.3- NA), but still showed a tendency to be longer than that in HR-positive patients (median: 9.1 months; 95% CI: 5.4-11.0). Patients with brain metastases at baseline could also benefit from this treatment (median PFS: 11.0; 95% CI: 5.4-NA). Consistent with the safety data reported before, the most common grade 3 or 4 treatment-related adverse events were leukopenia (68.3%), neutropenia (65.9%) and diarrhea (19.5%). Most adverse events were tolerable, and no study-related death reported. Conclusions: Combined with previous reports, our findings suggest dalpiciclib combined with pyrotinib achieved promising efficacy and manageable toxicity in the treatment of HER2-positive ABC, including patients with HR-negative disease or brain metastases. This combination could be considered as a completely oral, chemo-free regimen for patients with HER2-positive ABC and is worthy of further study. Clinical trial information: NCT04293276 .
Prognosis and trends in chemotherapy use for patients with stage IA triple-negative breast cancer (TNBC): A population-based study.
Authors: Paolo Tarantino, Julieta Leone, Carlos Teodoro Vallejo, Rachel A. Freedman, Adrienne Gropper Waks, Olga Martínez-Sáez, Ana Christina Garrido-Castro, Filipa Lynce, Nabihah Tayob, Nancy U. Lin, Sara M. Tolaney, Jose Pablo Leone
Journal: Journal of Clinical Oncology (2023)

510 Background: Outcomes for patients with stage IA TNBC in the modern era remain poorly characterized, and the benefit and utilization of adjuvant chemotherapy (chemo) in this setting remains controversial. Methods: We analyzed data from women diagnosed with pathological stage IA TNBC in the Surveillance, Epidemiology, and End Results (SEER) database during 2010 to 2019. We evaluated the associations of adjuvant chemo with breast-cancer specific survival (BCSS) stratified by tumor size, using multivariate cox models adjusted for tumor size (overall cohort only), age at diagnosis, race, tumor grade, histology, radiation, marital status, income, and rurality. Frequency of chemo use over time was examined by tumor size. Multivariate logistic regression assessed variables associated with chemo administration. Results: In total, we examined data from 8,601 women with stage IA TNBC. Median age at diagnosis was 62 years. Most patients had high-grade tumors (70.1%), ductal histology (92.8%), and received adjuvant chemo (61.6%). Median follow up was 48 months (IQR: 20 – 83). The use of chemo significantly increased during 2010-2019 for both T1b tumors (p for trend = 0.001) and T1c tumors (p for trend &lt; 0.001), with 52.5% and 63% of the patients with T1b and T1c TNBCs receiving chemo in 2010, respectively, compared with 60.5% and 71.1% in 2019. No significant differences were observed in the use of chemo for T1mic (p for trend = 0.567) and T1a (p for trend = 0.637) tumors, with low utilization seen in both cohorts (9.5% overall in T1mic, 22.5% overall in T1a). Variables associated with chemo use included younger age, white race, married status, higher income, more recent diagnosis, higher tumor grade, ductal histology, and larger tumor size (all p &lt; 0.02). Overall, 5-year BCSS was high across T groups ( &gt; 90%; Table). Receiving chemo (vs. none/unknown) was associated with an improved 5-year BCSS (adjusted HR for BCSS = 0.70, p = 0.006). For T1c tumors specifically, adjuvant chemo (vs. none/unknown) was also associated with BCSS (adjusted HR 0.64, p = 0.002). The small number of BCSS events precluded comparisons for other tumor size subgroups. Table shows sample sizes and 5-year BCSS rate by chemo receipt for each T group. Conclusions: In a large population-based cohort of patients with stage IA TNBC, we observed excellent 5-year BCSS outcomes, supporting the good prognosis of this patient population. The use of adjuvant chemo increased over time for T1b and T1c TNBCs, and was associated with improved BCSS for T1c tumors, although evaluation of benefit is limited by the inherent treatment bias in registry data. [Table: see text]
Trends in FDA approval of solid tumor therapies with analysis of single-agent vs. combination therapies.
Authors: Manoj P. Rai, Akshit Chitkara, Rajat Thawani, Emerson Yu-sheng Chen
Journal: Journal of Clinical Oncology (2023)

e13659 Background: Single agents replacing previous therapies are ideal, but combination therapies with two or more active agents have been proposed to decrease drug resistance, promote mechanistic synergy, and/or have additive cytotoxic effects in cancer treatment. However, approval of combination therapies may increase exposure to new and former drugs, leading to more costs and time commitments to patients. Methods: This retrospective analysis examines all FDA-approved drugs for malignant solid tumors from January 2011 to December 2022. We used the data presented in the package inserts on the US FDA website. At least two reviewers selected all new and clinically meaningful indication changes for data extraction. Drug approvals for topical medications, precancerous conditions, hematologic conditions, primarily pediatric cancers, primary genetic syndrome neoplasms, biosimilars, and minor indication changes were all excluded. The primary endpoint was the proportion of new approvals that replaced former therapies rather than adding to existing therapy to become multi-agent combinations. We also compared single and combination regimes with the differences regarding cancer types, line of therapy, primary endpoints leading to approval, year of approval, type of approval, and type of expedited programs at the FDA. Results: Our analysis identified 247 FDA solid tumor drug indication approvals among 279 drugs from 2011 to 2022, with non-small cell lung cancer (52, 21%), followed by breast cancer (28, 11.3%) and melanoma (22, 8.9%), being the most common. The most common class of drug was small molecular targeted therapies (99, 40%), followed by immunotherapy checkpoint inhibitors (84, 34%). Most approvals were for 1st line (111, 44.9%), followed by 2nd line (106, 42.9%), and adjuvant setting (17, 6.9%). Among 247 approvals, 167 (67.6%) replaced a former therapy to become a new single standard of cancer therapy for that clinical setting, while 80 (32%) added to an existing regimen as a combination. 32 (12.9%) approvals have 3 or more drugs in the new therapy, 49 (19.8%) with 2 drugs in the new therapy. When comparing single-agent vs. combination regimen approvals, there was difference in cancer types, type of regimen, line of therapy, highest endpoints leading to approval, novel therapy, and type of drug approval (p-value &lt; 0.05; test statistic &gt; critical value). However, the year of approval, fast-track, and priority-review status were not statistically significant. Conclusions: Approximately two-thirds (68%) of drug approvals over the past 12 years for non-hematologic solid cancers are replacing or adding a new standard. Still, a significant minority (32%) are adding to existing regimens increasing the complexity of cancer therapies, especially in highly prevalent solid tumors, increasing potential time commitment for patients, costs, and exposure to therapies with notable side effects.
A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer.
Authors: Weihong Zhao, Zheng Zhang, Yadi Zhang, Yimeng Chen, Yimin Zhu, Chuanling Liu, Jiakang Shao, Li Zhang, Mei Liu
Journal: Journal of Clinical Oncology (2023)

e13090 Background: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. The lack of specific targets leads in fewer effective treatments and poor prognosis. Immunotherapy has become a new generation of treatment approach in addition to surgery, radiotherapy, chemotherapy, endocrine therapy and targeted therapy. Immune checkpoint inhibitors (ICIs) have been widely used in the clinical treatment of various tumors and changed the landscape of tumor treatment, but the data from real-world studies of ICIs for TNBC remain limited. Methods: Clinical data of patients with advanced TNBC treated with ICIs in Chinese People’s Liberation Army General Hospital were collected from January 2004 to December 2022. The effect of different factors on patient response and prognosis was analyzed using Kaplan-Meier survival curves. The relationship between clinical, pathological characteristics, hematological indicators, and efficiency were analyzed using univariate and multifactorial Cox regressions. Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-free Survival (PFS), Overall survival (OS), and adverse events (AEs) were assessed. Results: Eighty-one patients were enrolled in the study. Median follow-up was 26.3 months (range, 16.0 - 36.6 months). Confirmed ORR was 32.1% and DCR was 64.2%. The median PFS was 4.2 months and the median OS was 11.0 months. Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 1, applying ICIs in 2 nd and later lines, with liver metastases, with more than two sites of metastases, lactate dehydrogenase (LDH) ≥ 194.3 U/L, alkaline phosphatase (ALP) ≥ 104.7 U/L, neutrophil-to-lymphocyte ratio at baseline (bNLR) ≥ 2.7, NLR before the second dose of immunotherapy (NLR2) ≥ 2.2, platelet to lymphocyte ratio before the second dose of immunotherapy (PLR2) ≥ 165.6 were associated with a poorer prognosis. Patients with effective initial treatment, tumor - infiltrating lymphocytes (TIL) ≥ 20%, derived neutrophil-to-lymphocyte ratio (dNLR) ≤ 1.9, LDH &lt; 194.3 U/L and bNLR &lt; 2.5 prior to ICI treatment have a better prognosis. Conclusions: ICIs were effective in advanced TNBC with tolerable adverse effects, and we have identified a series of biomarkers associated with PFS and OS. Randomized controlled clinical trials are warranted to validate our findings.
A single-arm phase 2 study of peri-operative immune checkpoint inhibition and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.
Authors: Heather L. McArthur, Elizabeth Anne Comen, Yolanda Bryce, Stephen Barnett Solomon, Jorge Henrique S. Leal, Christina DiLauro Abaya, Cristal Martinez, Reva K Basho, Philomena McAndrew, Brigid Larkin, David B. Page, Staci L. Mellinger, Nicole Fredrich, Nicole Moxon, Sangeetha M. Reddy, Meredith Carter, Sujata Patil, Basak Dogan, Margaret Elena Gatti-Mays, Larry Norton
Journal: Journal of Clinical Oncology (2023)

TPS635 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI) augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ICI [ipilimumab (ipi) +/- nivolumab (nivo)] was safe in patients (pts) with operable, early stage breast cancer (ESBC) and generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible women are ≥18y, with ER &lt;10%, PR &lt;10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. As of 2/14/21, 16/80 pts have been enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and received ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts received 3 additional doses of nivo at 240mg IV Q2 weeks. To reflect the US FDA approval of curative-intent pembrolizumab (pembro) in 2021, the protocol was recently amended to allow standard-of-care pembro as an alternative ICI option. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686 .
Results from the first step of a phase II study of vaccination with autologous dendritic cells loaded with autologous tumour homogenate in glioblastoma.
Authors: Laura Ridolfi, Lorena Gurrieri, Nada Riva, Jenny Bulgarelli, Francesco De Rosa, Massimo Guidoboni, Valentina Fausti, Nicoletta Ranallo, Marcella Tazzari, Massimiliano Petrini, Anna Maria Granato, Elena Pancisi, Flavia Foca, Monia Dall'Agata, Elena Amadori, Pietro Cortesi, Alessandro Gamboni, Giuseppe Pasini, Toni Ibrahim, Luigino Tosatto
Journal: Journal of Clinical Oncology (2023)

e14025 Background: Glioblastoma (GBM) is a poor prognosis malignant grade IV glioma. After surgical resection, standard therapy consists of concomitant radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Multiple phase I/II trials and at least 3 meta-analysis showed improved survival (OS) and progression free survival (PFS) with DC vaccination in High-grade gliomas (HGGs) patients (pts). In pts developing antitumor immunity, DC vaccination increases the amount of intratumoral activated cytotoxic T lymphocytes and decreases the number of FoxP3 positive regulatory T cells. Based on these data we have developed a phase II protocol with DC vaccine concomitant to standard RT-CT in pts who have undergone radical surgery for GBM. Methods: This is a single-arm, monocentric, phase II trial of a DC vaccination integrated to standard therapy in resected GBM pts. All pts receive a dendritic cell vaccine loaded with autologous tumor homogenate for up to one year. The vaccine administration starts at the end of the RT-CT (Induction Phase) and then is alternated to TMZ cycles (Maintenance Phase). Primary end points are PFS and safety, among secondary end points there are the in vitro (Elispot, Plasma Cytokines, Tumor tissue analysis) and in vivo (DTH skin test) Immune response evaluations. A Simon's two-stage design has been used for the sample size calculation. In the first stage, 9 patients have been accrued and a total of 28 patients will be enrolled at the end of the second step. Results: From July 2021, the 9 pts of the first step has been enrolled, 4 females and 5 males with median age of 58 years. Five pts had no MGMT mutation. All 9 pts concluded the induction phase. To November 2022 four pts have progressed with a median PFS, from the date of leukapheresis, of 6.5 months (3.2-NE). DTH test became positive in 5 out of 9 evaluable pts. Median OS from the date of surgery was 11 months. No gr 3-4 vaccine related toxicities have been observed and gr 1-2 toxicities were mostly due to local skin reactions. Conclusions: On the basis of the results described above and the vaccine favorable toxicity profile the Study Team decided to proceed with the second step. Clinical trial information: EUCTR220-003755-15 . [Table: see text]
CASSIOPE: A prospective noninterventional study of cabozantinib treatment following prior vascular endothelial growth factor (VEGF) -targeted therapy in patients with advanced renal cell carcinoma (aRCC).
Authors: Michael D. Staehler, Pierre Bigot, Philippe Barthelemy, Paul Hamberg, Cristina Suárez, Jean-Christophe Eymard, Pablo Gajate, Valérie Perrot, Bryan Qvick, Pascale Dutailly, Giuseppe Procopio
Journal: Journal of Clinical Oncology (2023)

4529 Background: Cabozantinib is a tyrosine kinase inhibitor approved as monotherapy for aRCC in the USA, and as first-line therapy for patients with intermediate or poor risk aRCC, or after previous VEGF-targeted therapy in Europe. In the METEOR trial, a substantial proportion of patients required cabozantinib dose modifications. We report a real-world study of cabozantinib use for aRCC. Methods: CASSIOPE was a non-interventional prospective cohort study (conducted Apr 2018–May 2022; NCT03419572). Enrollment spanned 11 European countries (91 sites) where cabozantinib is marketed for aRCC. Patients had aRCC and had received ≥ 1 prior VEGF-targeted therapy (excluding cabozantinib). Decision to initiate cabozantinib was made prior to enrolment. The primary endpoint was cabozantinib usage (dose interruptions, reductions or discontinuations due to AEs) in the second- (2L) or later- (≥ 3L) line settings. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability. Data were analyzed descriptively for patients with safety follow-up after ≥ 1 cabozantinib dose. Results: In total, 679 patients were included (73.0% male; median [range] age 67.0 [29–93] yrs; 85.7% clear-cell aRCC; 80.3% prior nephrectomy). Median (range) observation period was similar for 2L (n = 335; 8.51 [0.2–15.4] mo) and ≥ 3L cabozantinib (n = 343; 9.26 [0.0–15.0] mo). Usage data are shown. For the overall population, ORR (95% CI) and median (95% CI) PFS according to local assessment were 21.9% (17.5%–26.9%) and 7.8 (6.3–8.7) mo for 2L cabozantinib, and 38.0% (32.7%–43.5%) and 8.7 (7.6–9.6) mo for ≥ 3L cabozantinib. Median OS (95% CI) was 13.0 (12.6–not calculated [NC]) mo for 2L, and 17.1 (13.8–NC) mo for ≥ 3L cabozantinib. Most patients (90.4%) reported treatment-related AEs (Grade 1, 71.1%; Grade 2, 70.3% of patients), most commonly any grade diarrhea (52.4%), palmar-plantar erythrodysesthesia syndrome (27.2%), decreased appetite (25.5%), hypertension (21.9%), asthenia (21.6%), fatigue (20.5%) and nausea (20.3%). Conclusions: In this real-world study, tolerability of ≥ 2L cabozantinib was consistent with the METEOR trial safety profile: cabozantinib dose modifications due to AEs were common, but discontinuation rates due to AEs were substantially less frequent. Cabozantinib activity was maintained across lines. Clinical trial information: NCT03419572 . [Table: see text]
State-of-the-art management of HER2-negative early breast cancer: Treatment patterns among healthcare professionals and concordance with expert recommendations.
Authors: Marie N. Becker, Jame Abraham, Kevin Kalinsky, Laura Spring, Tiffany A. Traina, Timothy A. Quill, Denise A. Yardley
Journal: Journal of Clinical Oncology (2023)

553 Background: The management of high-risk HER2-negative early-stage breast cancer (EBC) has recently evolved with the addition of newer agents including abemaciclib, olaparib, and pembrolizumab as (neo)adjuvant therapy options for appropriate patients. To aid healthcare professionals (HCPs) in the recommended implementation of these agents, we developed an online treatment decision support tool providing case-specific treatment guidance from 5 breast cancer experts. Here, we report an analysis of cases entered into the tool by HCPs, comparing their planned treatment with expert recommendations. Methods: Expert therapy recommendations for 10 case scenarios in high-risk HER2-negative EBC based on 3 pivotal clinical trials (KEYNOTE-522, OlympiA, and monarchE) were obtained in March 2022. Patient and disease characteristics included hormone receptor (HR) status, BRCA mutational status, lymph node positivity, presence of residual disease after resection, and additional criteria based on the 3 practice-changing trials. HCPs entered specific patient and disease factors into the tool along with their intended treatment plan and were shown 5 individual expert treatment recommendations for the unique case scenario. Results: From June 2022 to January 2023, 547 HCPs entered 982 patient case scenarios into the tool. A comparison of treatment recommendations by experts and HCPs showed divergence for several case scenarios. For patients with high-risk HR-positive/HER2-negative EBC and no BRCA mutation, all 5 experts recommended adjuvant abemaciclib plus endocrine therapy. By contrast, 64% of HCPs’ therapy choices were discordant with the experts, with 49% choosing chemotherapy followed by endocrine therapy. For patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy and have no residual disease, all 5 experts recommended observation, whereas 36% of HCPs recommended additional adjuvant therapy. In the setting of BRCA-mutated TNBC with residual disease after neoadjuvant pembrolizumab plus chemotherapy, 4 of 5 experts recommended adjuvant pembrolizumab plus olaparib, but just 33% of HCPs chose this combination. One third of HCPs who initially selected treatment options that diverged from expert recommendations or who were uncertain about treatment choice intend to change their therapy selection to align with the experts. Conclusions: Analysis of data from this tool suggests differences in clinical practice between experts and HCPs for multiple case scenarios of high-risk EBC, including examples of potential overtreatment. Moreover, our data demonstrate that this decision support tool may lead to better alignment of HCP treatment choices with experts, with the potential to improve clinical management of patients.